An FGF signaling loop sustains the generation of differentiated progeny from stem cells in mouse incisors

Klein, Ophir D.; Lyons, David; Balooch, Guive; Marshall, Grayson W.; Basson, M. Albert; Peterka, Miroslav; Boran, Tomas; Peterková, Renata; Martin, Gail R.

doi:10.1242/dev.015081

Cited by 159 publications

(227 citation statements)

References 29 publications

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“…Here, we hypothesized that members of the Sprouty family, which encode intracellular RTK signaling inhibitors essential for numerous vertebrate developmental processes (27)(28)(29)(30), regulate EGFR signaling in the mammary gland stroma. To test this hypothesis, we determined the mammary gland phenotype in mice lacking sprouty 1 (Spry1) and analyzed the mechanisms by which SPRY1 functions.…”

Section: Significancementioning

confidence: 99%

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

Koledová

Zhang

Streuli

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The role of the local microenvironment in influencing cell behavior is central to both normal development and cancer formation. Here, we show that sprouty 1 (SPRY1) modulates the microenvironment to enable proper mammary branching morphogenesis. This process occurs through negative regulation of epidermal growth factor receptor (EGFR) signaling in mammary stroma. Loss of SPRY1 resulted in up-regulation of EGFR-extracellular signal-regulated kinase (ERK) signaling in response to amphiregulin and transforming growth factor alpha stimulation. Consequently, stromal paracrine signaling and ECM remodeling is augmented, leading to increased epithelial branching in the mutant gland. By contrast, down-regulation of EGFR-ERK signaling due to gain of Sprouty function in the stroma led to stunted epithelial branching. Taken together, our results show that modulation of stromal paracrine signaling and ECM remodeling by SPRY1 regulates mammary epithelial morphogenesis during postnatal development.branching morphogenesis | FGF signaling | EGF signaling | epithelial-stromal interactions | stromal microenvironment A central theme in developmental and cancer biology research is to understand the mechanisms by which the local microenvironment, or niche, influences fundamental aspects of cell and tissue behavior during organ formation and function (1). The importance of mesenchyme, as the embryonic niche, in determining organ identity and fate of the epithelium was demonstrated long ago by classic embryological studies (2, 3). More recent studies have shown, however, that postnatal stroma, a derivative of embryonic mesenchyme, is essential for maintenance of cell fate and differentiation status in adult life (4, 5). Indeed, abnormal stroma can lead to the formation of a cancer microenvironment, and it plays a causative role during tumor onset and progression (1, 6). As such, understanding postnatal stromal biology and the mechanism by which its deregulation may promote tumorigenesis is of key importance.The mouse mammary gland is a powerful model for understanding the genetic and cellular basis of stromal biology (7). The observation that epithelial branching of the mammary gland persists for many weeks after birth has made amenable the detection of stromal influences on epithelial invasion and patterning (8, 9). Indeed, postnatal mammary stroma is composed of many cell types, including periductal fibroblasts and white adipocytes, endothelial cells, nerve cells, and a variety of infiltrating immune cells, including macrophages and eosinophils, which play an important role in postnatal branching (10).Mammary stroma regulates epithelial branching by at least two mechanisms. Stromal cells produce several paracrine factors, including fibroblast growth factors (FGFs) and insulin-like growth factor (IGF) that activate receptor tyrosine kinases (RTK) (11, 12). For example, a reduction in FGF signaling due to loss of FGF10 or its receptor FGF receptor 1/2 (FGFR1/2), or reduced IGF signaling, leads to stunted epithelial branching (13-16). B...

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Section: Significancementioning

confidence: 99%

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

Koledová

Zhang

Streuli

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Fgf10 is the key mesenchymal signal required for epithelial stem cell maintenance and proliferation, and Fgf3 has a partly redundant function as stimulator of TA cell proliferation (Wang et al 2007). Mesenchymal Fgfs act in a regulatory loop with epithelial Fgfs, notably Fgf9, and stimulation of Fgf signaling by deleting the function of Sprouty genes results in extensive growth of the incisors and ectopic deposition of enamel on the lingual surface (Klein et al 2008). Lingual enamel also forms in Follistatin knockout mice, whereas enhanced Follistatin expression results in complete absence of enamel from labial side as well as in growth inhibition .…”

Section: Regulation Of Tooth Replacement Continuous Growth and Stemmentioning

confidence: 99%

Signaling Networks Regulating Tooth Organogenesis and Regeneration, and the Specification of Dental Mesenchymal and Epithelial Cell Lineages

Jussila

Thesleff²

2012

Cold Spring Harbor Perspectives in Biology

225

209

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SUMMARYTeeth develop as ectodermal appendages from epithelial and mesenchymal tissues. Tooth organogenesis is regulated by an intricate network of cell -cell signaling during all steps of development. The dental hard tissues, dentin, enamel, and cementum, are formed by unique cell types whose differentiation is intimately linked with morphogenesis. During evolution the capacity for tooth replacement has been reduced in mammals, whereas teeth have acquired more complex shapes. Mammalian teeth contain stem cells but they may not provide a source for bioengineering of human teeth. Therefore it is likely that nondental cells will have to be reprogrammed for the purpose of clinical tooth regeneration. Obviously this will require understanding of the mechanisms of normal development. The signaling networks mediating the epithelial-mesenchymal interactions during morphogenesis are well characterized but the molecular signatures of the odontogenic tissues remain to be uncovered. Outline

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“…[60][61][62] Knockout mice of different Spry family members have uncovered non-overlapping and essential roles during development and postnatal maturation in many tissues and organs, including neural, ear, kidney and teeth. 57,58,[63][64][65] Spry has been implicated in developmental myogenesis. 66,67 Gain-of-function experiments demonstrated that Spry2, promoted a shift in fate of myogenic cells, favoring a less differentiated Pax3/7-expressing population at the expense of a more differentiated myogenin-expressing population.…”

Section: Models Of Reversible Quiescencementioning

confidence: 99%

Muscle stem cells and reversible quiescence: The role of sprouty

Abou-Khalil¹,

Brack²

2010

Cell Cycle

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An FGF signaling loop sustains the generation of differentiated progeny from stem cells in mouse incisors

Cited by 159 publications

References 29 publications

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling

Signaling Networks Regulating Tooth Organogenesis and Regeneration, and the Specification of Dental Mesenchymal and Epithelial Cell Lineages

Muscle stem cells and reversible quiescence: The role of sprouty

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